Growth factors can be broadly defined as multifunctional, intercellular signaling polypeptides that control both the ontogeny and maintenance of tissue form and function. Growth factors may act locally or at a distance, and they share a number of common biological properties. They often exert their biological actions at very low concentrations because their action is mediated by their association with specific, high-affinity receptors expressed by the target cell type. The function of the growth factor receptor is not only to interact specifically with the ligand on the outside of the cell but also to generate an intracellular signal on the inside of the cell. This generation of growth factor receptor-mediated intracellular signals, and their interpretation by the responding cell, leads to the modification of target cell behavior. Some growth factors are highly restricted in the range of cells on which they act, whereas others can regulate the behavior of many different cell types. Some growth factors are found to be widespread in their expression and distribution in the developing embryo and fully developed adult. The biological actions of growth factors are not confined to the regulation of cell replication, but can extend to a wide variety of cell functions including differentiation, migration and gene expression.
Growth factors have generally been first identified by their ability to stimulate proliferation in cell cultures that have become quiescent as a result of contact inhibition. Most have been isolated from mammalian sources and have been identified by their effects on mammalian cells. Some growth factor-like molecules have been identified in Drosophila by homology searching and by genetic analysis. Examples include the EGF-related products of the spitz (Schweitzer, et al., Genes Dev., 9:1518, 1995) and gurken (Neuman-Silverberg, et al., Cell, 75:165, 1993) genes; and the TGF-.beta. family member produced by the dpp gene (Cohen, Development, 107:65, 1989). However, none of these has been clearly shown to have mitogenic activity as expected of a growth factor.
Drosophila larvae have ten pairs of imaginal discs which give rise to the eyes/antennae, the legs, the halteres, the wings, various head structures and a single genital disc. Imaginal discs develop from patches of cells that proliferate extensively during larval development. Cell proliferation in imaginal discs is regulated locally by cell interactions as part of the mechanism that leads to the development of spatial patterns of differentiation within the Drosophila epithelium (Hakala, et al., J. Biol. Chem. 268:25803, 1993). These interactions are known to involve signaling pathways mediated by secreted factors which include the products of the hh (Capdevila, et al., EMBO J., 13:4459, 1994), dpp (Pignoni, et al., Development, 124:271, 1997) and wg (Neumann, et al., Development, 122:1781, 1996) genes. Such factors lead to excess cell proliferation when ectopically expressed, but these effects are localized and may be an indirect result of effects on patterning rather than an indication of conventional growth-factor activity. Growth factors as defined in the mammalian cell paradigm have not been previously identified from invertebrates.